Kruppel-Like Transcription Factors Proteins

Kruppel-like factors (KLFs) belong to a group of transcription factors that contain conserved zinc (Zn)-finger domains in their C-terminal regions that bind to target DNA sequences. KLFs share homology with Sp1-like transcription factors, one of the first transcription factors to be identified and classified. Subsequently, other Zn-finger containing transcription factors like KLF proteins were identified. This nomenclature Kruppel, came from drosophila which means “cripple” in German, as a critical mutation in drosophila, led to their severe body malformation. These KLF transcription factors are important constituents of the eukaryotic transcriptional machinery in cells. KLF proteins regulate the gene expression of a wide variety of genes.

Fig.1 Schematic comparison of various domains of KLFs

KLF proteins are critical regulators of physiological systems including cardiovascular, hematological, respiratory, digestive, and immune system. They are involved in disorders like cardiovascular disease, cancer, obesity and inflammatory diseases. KLF-like factors also regulate key physiological processes in the kidney, which range from maintaining glomerular filtration barrier to tubulointerstitial inflammation to progression of kidney fibrosis. Gene expression arrays from deep sequencing of microdissected nephron segments of rat renal cortex demonstrated the expression pattern of various KLF proteins in the kidney.

KLF4 is expressed in podocytes and is a critical regulator of proteinuria. In proteinuric animals and humans, decreased KLF4 expression contributes to proteinuria. Gene transfer by tail vein injections or podocyte-specific transgenic restoration of KLF4 in diseased glomeruli, induced recovery of podocyte epithelial marker nephrin with a concurrent decrease in albuminuria. Moreover, adriamycin-induced proteinuria was found to be significantly exacerbated in podocyte-specific KLF4 KO mice. The mechanism by which KLF4 regulated expression of nephrin gene and other epithelial and mesenchymal genes was shown to involve epigenetic modification of promoters of these genes.

KLF6 is also expressed in the podocytes and is critical for preservation of mitochondrial function and prevention of podocyte apoptosis. KLF6 expression is decreased in renal biopsies of patients with HIV-associated nephropathy (HIVAN) and focal segmental glomerulosclerosis (FSGS). Additionally, loss of KLF6 in podocyte-specific KLF6 KO mice increased susceptibility of a resistant mouse strain to adriamycin-induced FSGS. KLF6 regulated the mitochondrial function by modulating expression of its target protein mitochondrial cytochrome c oxidase assembly gene (SCO2). Over-expression of KLF5 in podocytes prevented PAN-induced cell cycle arrest and podocyte apoptosis by blocking the activation of ERK/p38 MAPK pathways.

Various KLF proteins regulate different aspects of kidney disease. Specific KLF proteins could serve as therapeutic targets and agents that increase or decrease expression and/or function of specific KLF proteins, could serve as drugs to ameliorate kidney injury and/or slow down or halt progression to fibrosis and CKD. Epigenetic modifications of genes play a critical role in renal fibrosis and CKD. In the future epigenetic modification drugs that induce KLF4 expression could serve as good candidate for treatment of CKD. KLF4 and KLF6 expression is decreased in renal cell carcinoma, there by promoting cellular proliferation and metastasis.

In addition to cells of the vessels themselves, circulating immune cells and their infiltration into the vascular wall are paramount to the initiation and propagation of vascular inflammation. There is ample research implicating both innate and adaptive immune cells in the progression of atherosclerosis. Comparable with their role in vascular cells, KLFs have divergent functions in myeloid cell-derived inflammation, capable of either repressing or promoting inflammatory processes.

Fig.2 Select effector functions of myeloid KLFs

In addition to regulating differentiation, activation, and polarization of monocytes, KLFs also shape lymphocyte and DC function. While there is a paucity of studies investigating KLF-driven lymphocyte processes in vascular inflammation, there is extensive evidence demonstrating the importance of KLFs in lymphocyte biology that can be extrapolated to the context of vascular disease.

Current therapies for atherosclerosis largely target mechanisms known to activate vascular inflammatory cascades such as dyslipidemia (statins), disturbed flow (anti-hypertensives), and activated circulating inflammatory cells (aspirin). Given the importance of these stimuli in the pathogenesis of atherosclerosis and thrombosis, understanding molecular mediators of vascular inflammation is imperative in developing novel agents against cardiovascular disease. While accomplishing specificity in targeting KLFs will likely be difficult, multiple compounds act upstream of KLFs, thereby modulating their expression and function.

Miller I.J., Bieker J.J. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Mol Cell Biol. 1993;13(5):2776–2786.

Pei J., Grishin N.V. A new family of predicted krüppel-like factor genes and pseudogenes in placental mammals. PLoS One. 2013;8(11)